{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T16:20:32Z","timestamp":1784305232508,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the UAEU (United Arab Emirates University) Program for Advanced Research (UPAR)","award":["G00004174"],"award-info":[{"award-number":["G00004174"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is known to increase the risk of fragility fractures; however, the underlying mechanism is still elusive. Reduced miR-155 and elevated RHOA are known to drive bone resorption, but their role in T2DM remains unclear. This study investigates bone remodeling imbalances in T2DM through miR-155 and RHOA expression profiling. Three-month-old female Wistar rats were fed a high-calorie diet for 3 weeks, followed by intraperitoneal injections of two lower doses of streptozotocin at weekly intervals to induce T2DM. Bone analysis from diabetic rats tested using qRT-PCR showed significantly reduced miR-155 levels and elevated RHOA. Histological analysis showed a 12.65% increase in Tb.Sp, 10.07% decrease in Tb.Th, and significant increase (p &lt; 0.05) in apoptotic osteocytes. The bone turnover marker CTx-1 level was increased by 20.84%, and RANKL levels were significantly increased in T2DM. IL-1\u03b2 and TNF-\u03b1 were increased in T2DM. Bone resorption is more likely to occur in T2DM as both IL-1\u03b2 and TNF-\u03b1 work synergistically to promote osteoclastogenesis. MiR-155 could be an important modulator of bone remodeling in T2DM and a potential therapeutic target for diabetic osteopathy.<\/jats:p>","DOI":"10.3390\/ijms26178159","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:47:49Z","timestamp":1755870469000},"page":"8159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bone Microstructural Deterioration and miR-155\/RHOA-Mediated Osteoclastogenesis in Type 2 Diabetes Mellitus"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6537-5802","authenticated-orcid":false,"given":"Mouza M.","family":"Alaleeli","sequence":"first","affiliation":[{"name":"Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suneesh","family":"Kaimala","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-1562","authenticated-orcid":false,"given":"Ernest","family":"Adeghate","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-6048","authenticated-orcid":false,"given":"Sahar","family":"Mohsin","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., Ostolaza, H., and Mart\u00edn, C. (2020). Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176275"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.cmet.2019.03.009","article-title":"Epigenetics in Human Obesity and Type 2 Diabetes","volume":"29","author":"Ling","year":"2019","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202-LB","DOI":"10.2337\/db18-202-LB","article-title":"Global Prevalence of Type 2 Diabetes over the Next Ten Years (2018\u20132028)","volume":"67","author":"Kaiser","year":"2018","journal-title":"Diabetes"},{"key":"ref_4","first-page":"1303","article-title":"Prevalence of type 2 diabetes in the Arab world: Impact of GDP and energy consumption","volume":"21","author":"Meo","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9342696","DOI":"10.1155\/2020\/9342696","article-title":"Osteoporosis and Fragility Fractures in Type 2 Diabetes","volume":"2020","author":"Chiodini","year":"2020","journal-title":"J. Diabetes Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/1350-4533(96)00011-2","article-title":"Quantitative CT in the measurement of bone quantity and bone quality for assessing osteoporosis","volume":"18","author":"Dougherty","year":"1996","journal-title":"Med. Eng. Phys."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Stevens, M.R., Ghasemi, S., and Tabrizi, R. (2021). Bone Quantity BT\u2014Innovative Perspectives in Oral and Maxillofacial Surgery, Springer International Publishing.","DOI":"10.1007\/978-3-030-75750-2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1590\/S0004-27302006000400003","article-title":"Bone quality: What is it and how is it measured?","volume":"50","author":"Compston","year":"2006","journal-title":"Arq. Bras. De Endocrinol. Metabol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3876957","DOI":"10.1155\/2019\/3876957","article-title":"Type 2 diabetes mellitus increases the risk to hip fracture in postmenopausal osteoporosis by deteriorating the trabecular bone microarchitecture and bone mass","volume":"2019","author":"Mohsin","year":"2019","journal-title":"J. Diabetes Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e135236","DOI":"10.1172\/jci.insight.135236","article-title":"Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes","volume":"5","author":"Eckhardt","year":"2020","journal-title":"JCI Insight"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11914-014-0194-3","article-title":"Apoptotic osteocytes and the control of targeted bone resorption","volume":"12","author":"Plotkin","year":"2014","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"775","DOI":"10.4049\/jimmunol.138.3.775","article-title":"Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption","volume":"138","author":"Thomson","year":"1987","journal-title":"J. Immunol."},{"key":"ref_13","first-page":"15","article-title":"Interleukin-1 beta stimulates bone resorption and inhibits bone formation in vivo","volume":"10","author":"Nguyen","year":"1991","journal-title":"Lymphokine Cytokine Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cytogfr.2003.10.005","article-title":"IL-6, RANKL, TNF-alpha\/IL-1: Interrelations in bone resorption pathophysiology","volume":"15","author":"Steeve","year":"2004","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.mpmed.2013.07.014","article-title":"Osteoporosis","volume":"41","author":"Eastell","year":"2013","journal-title":"Medicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.diabet.2011.11.006","article-title":"Inflammation and type 2 diabetes","volume":"38","author":"Calle","year":"2012","journal-title":"Diabetes Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"165852","DOI":"10.1016\/j.bbadis.2020.165852","article-title":"Osteoclast signaling-targeting miR-146a-3p and miR-155-5p are downregulated in Paget\u2019s disease of bone","volume":"1866","author":"Stephens","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s10020-023-00638-1","article-title":"RhoA promotes osteoclastogenesis and regulates bone remodeling through mTOR-NFATc1 signaling","volume":"29","author":"Wang","year":"2023","journal-title":"Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6910312","DOI":"10.1155\/2020\/6910312","article-title":"RANKL\/RANK\/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling","volume":"2020","author":"Tobeiha","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"782382","DOI":"10.1155\/2015\/782382","article-title":"The role of IL-1\u03b2 in the bone loss during rheumatic diseases","volume":"2015","author":"Ruscitti","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.4049\/jimmunol.138.5.1464","article-title":"Synergistic interactions between interleukin 1, tumor necrosis factor, and lymphotoxin in bone resorption","volume":"138","author":"Stashenko","year":"1987","journal-title":"J. Immunol."},{"key":"ref_22","unstructured":"Nelson, D.L., and Cox, M.L. (2005). Regulation of Gene Expression. Lehninger Principles of Biochemistry, W.H. Freeman and Company. [4th ed.]."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6773","DOI":"10.1128\/MCB.00941-08","article-title":"MicroRNA-155 Is Regulated by the Transforming Growth Factor \u03b2\/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA","volume":"28","author":"Kong","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","first-page":"268","article-title":"The OPG\/RANKL\/RANK system in metabolic bone diseases","volume":"4","author":"Hofbauer","year":"2004","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.abb.2008.03.018","article-title":"Functions of RANKL\/RANK\/OPG in bone modeling and remodeling","volume":"473","author":"Boyce","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"901616","DOI":"10.3389\/fendo.2022.901616","article-title":"The role of interleukin-1\u03b2 in type 2 diabetes mellitus: A systematic review and meta-analysis","volume":"13","author":"Alfadul","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/cdd.2015.176","article-title":"Inflammasome-dependent IL-1\u03b2 release depends upon membrane permeabilisation","volume":"23","author":"Diamond","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s005920050142","article-title":"Bone metabolism in type 2 diabetes mellitus","volume":"36","author":"Isaia","year":"1999","journal-title":"Acta Diabetol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1177\/154405910608500606","article-title":"Diabetes enhances periodontal bone loss through enhanced resorption and diminished bone formation","volume":"85","author":"Liu","year":"2006","journal-title":"J. Dent. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1210\/jcem.87.7.8480","article-title":"Ethnic variation in bone turnover in pre-and early perimenopausal women: Effects of anthropometric and lifestyle factors","volume":"87","author":"Finkelstein","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00592-011-0347-0","article-title":"Serum levels of bone resorption markers are decreased in patients with type 2 diabetes","volume":"50","author":"Varsavsky","year":"2013","journal-title":"Acta Diabetol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12902-017-0224-0","article-title":"Low bone turnover in premenopausal women with type 2 diabetes mellitus as an early process of diabetes-associated bone alterations: A cross-sectional study","volume":"17","author":"Purnamasari","year":"2017","journal-title":"BMC Endocr. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e111703","DOI":"10.1371\/journal.pone.0111703","article-title":"Relationship of Dickkopf1 (DKK1) with Cardiovascular Disease and Bone Metabolism in Caucasian Type 2 Diabetes Mellitus","volume":"9","author":"Kirchmair","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.diabres.2008.07.008","article-title":"Increased bone resorption may play a crucial role in the occurrence of osteopenia in patients with type 2 diabetes: Possible involvement of accelerated polyol pathway in its pathogenesis","volume":"82","author":"Takizawa","year":"2008","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"569563","DOI":"10.1155\/2014\/569563","article-title":"Oxidative stress and bone resorption interplay as a possible trigger for postmenopausal osteoporosis","volume":"2014","author":"Cervellati","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_36","unstructured":"(2025, May 01). The Chinese University of Hong Kong, \u201cID: MIRT000949,\u201d miRTarBase. Available online: https:\/\/mirtarbase.cuhk.edu.cn\/~miRTarBase\/miRTarBase_2025\/php\/index.php."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.bbrc.2019.04.030","article-title":"NIPA2 regulates osteoblast function via its effect on apoptosis pathways in type 2 diabetes osteoporosis","volume":"513","author":"Zhao","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.mpmed.2018.10.010","article-title":"What is type 2 diabetes?","volume":"47","author":"Hurtado","year":"2018","journal-title":"Medicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19596","DOI":"10.3402\/ijch.v72i0.19596","article-title":"Clinical risk factors for osteoporosis are common among elderly people in Nuuk, Greenland","volume":"72","author":"Jakobsen","year":"2013","journal-title":"Int. J. Circumpolar Health"},{"key":"ref_40","unstructured":"Loh, H.Y., Lau, Y.Y., Lai, K.S., and Osman, M.A. (2018). MicroRNAs in Bone Diseases: Progress and Prospects. Transcriptional and Post-Transcriptional Regulation, Intechopen."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2","DOI":"10.2174\/2211536611201010002","article-title":"MicroRNA-155 functions as a negative regulator of RHOA signaling in TGF-\u03b2-induced endothelial to mesenchymal transition","volume":"1","author":"Bijkerk","year":"2012","journal-title":"MicroRNA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"104933","DOI":"10.1016\/j.jmbbm.2021.104933","article-title":"Trabecular bone porosity and pore size distribution in osteoporotic patients\u2013A low field nuclear magnetic resonance and microcomputed tomography investigation","volume":"125","author":"Porrelli","year":"2022","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1001\/jama.298.20.2381","article-title":"High-Trauma Fractures and Low Bone Mineral Density in Older Women and Men","volume":"298","author":"Mackey","year":"2007","journal-title":"JAMA"},{"key":"ref_44","unstructured":"Cvijanovi\u0107, O., Crn\u010devi\u0107-Orli\u0107, \u017d, Kristofi\u0107, I., \u0160panjol, J., Zori\u010di\u0107, S., Mari\u0107, I., and Bobinac, D. (2001). Trabecular bone volume and bone mineral density correlation in lumbar spine. 1st Joint Meeting of the International Bone and Mineral Society and the European Calcified Tissue Society, Elsevier."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41419-020-03059-8","article-title":"Osteocyte apoptosis: The roles and key molecular mechanisms in resorption-related bone diseases","volume":"11","author":"Ru","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/jre.12875","article-title":"The miR-155-5p inhibits osteoclast differentiation through targeting CXCR2 in orthodontic root resorption","volume":"56","author":"Jiang","year":"2021","journal-title":"J. Periodontal Res."},{"key":"ref_47","first-page":"1431","article-title":"The laboratory rat: Age and body weight matter","volume":"20","author":"Ghasemi","year":"2021","journal-title":"EXCLI J."},{"key":"ref_48","first-page":"424","article-title":"The laboratory rat as an animal model for osteoporosis research","volume":"58","author":"Lelovas","year":"2008","journal-title":"Comp. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.phrs.2005.05.004","article-title":"Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening","volume":"52","author":"Srinivasan","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"704045","DOI":"10.1155\/2008\/704045","article-title":"The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model","volume":"2008","author":"Zhang","year":"2008","journal-title":"J. Diabetes Res."},{"key":"ref_51","first-page":"444","article-title":"Fractures of the femur and tibial shaft","volume":"34","author":"Yates","year":"2016","journal-title":"Surgery"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:04Z","timestamp":1760034844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178159"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178159","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}